Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
  • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
  • A61K31/5578—Eicosanoids, e.g. leukotrienes or prostaglandins having a pentalene ring system, e.g. carbacyclin, iloprost
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/06—Antiglaucoma agents or miotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives

Definitions

• the invention is concerned with the use of prostaglandin derivatives of PGA, PGB, PGD, PGE and PGF, in which the omega chain has been modified with the common feature of containing a ring structure, for the treatment of glaucoma or ocular hypertension.
• the invention relates also to ophthalmic compositions, containing an active amount of these prostaglandin derivatives, and the manufacture of such compositions.
• Glaucoma is an eye disorder characterized by increased intraocular pressure, excavation of the optic nerve head and gradual loss of the visual field.
• An abnormally high intraocular pressure is commonly known to be detrimental to the eye, and there are clear indications that, in glaucoma patients, this probably is the most important factor causing degenerative changes in the retina.
• the pathophysiological mechanism of open angle glaucoma is, however, still unknown. Unless treated successfully glaucoma will lead to blindness sooner or later, its course towards that stage is typically slow with progressive loss of the vision.
• IOP intraocular pressure
• P e the episcleral venous pressure, generally regarded as being around 9 mm Hg
• F the flow of aqueous humor
• R the resistance to outflow of aqueous humor through the trabecular meshwork and adjacent tissue into Schlemm's canal.
• canal aqueous humor might also pass through the ciliary muscle into the suprachoroidal space and finally leave the eye through sclera.
• This uveoscleral route has been described for instance by Bill (1975).
• the pressure gradient in this case is insignificant compared to the gradient over the interior wall of Schlemm's canal and adjacent tissue in the former case.
• the flow limiting step along the uveoscleral route is assumed to be the flow from the anterior chamber into the suprachoroidal space.
• IOP P e + (F t - F u ) x R
• P e and R are defined as above
• F t is the total outflow of aqueous humor
• F u is the fraction passing via the uveoscleral route.
• IOP in human beings is normally in the range of 12 - 22 mm Hg. At higher values, for instance over 22 mm Hg, there is a risk that the eye may be affected. In one particular form of glaucoma, low tension glaucoma, damage may occur at intraocular pressure levels otherwise regarded as physiologically normal. The reason for this could be that the eye in these individuals is unusually sensitive to pressure. The opposite situation is also known, that some individuals may exhibit an abnormally high intraocular pressure without any manifest defects in the visual field or optic nerve head. Such conditions are usually referred to as ocular hypertension.
• Glaucoma treatments can be given by means of drugs, laser or surgery.
• drug treatment the purpose is to lower either the flow (F) or the resistance (R) which, according to formula (1) above, will result in a reduced IOP; alternatively to increase the flow via the uveoscleral route which according to formula (2) also gives a reduced pressure.
• Cholinergic agonists for instance pilocarpine, reduce the intraocular pressure mainly by increasing the outflow through Schlemm's canal.
• Prostaglandins which recently have met an increasing interest as IOP-lowering substances may be active in that they will cause an increase in the uveoscleral outflow (Crawford et al, 1987, and Nilsson et al, 1987). They do not appear, however to have any effect on the formation of aqueous humor or on the conventional outflow through Schlemm's canal (Crawford et al, 1987).
• prostaglandins and their derivatives are described for instance in US 4599353 and EP 87103714.9, and by Bito LZ et al (1983), Camras CB et al (1981, 1987a, 1987b, 1988), Giuffrè G (1985), Kaufman PL (1986), Kersetter JR et al (1988), Lee P-Y et al (1988) and Villumsen J et al (1989).
• prostaglandins and derivatives as suitable drugs for treating glaucoma or ocular hypertension, a limiting factor is their property of causing superficial irritation and vasodilation in the conjunctiva. It is probable, moreover, that prostaglandins have an irritant effect on the sensory nerves of the cornea. Thus local side effects will arise in the eye already when the amounts of prostaglandin administered are quite small - that is, already when the doses are lower than those that would be desirable for achieving maximum pressure reduction. It has thus been found, for instance, that for this reason it is clinically impossible to use PGF 2 ⁇ -1-isopropyl ester in the amount that would give maximum pressure reduction.
• Prostaglandins being naturally occurring autacoids, are very potent pharmacologically and affect both sensory nerves and smooth muscle of the blood vessels. Since the effects caused by administrations of PGF 2 ⁇ and its esters to the eye, comprise in addition to pressure reduction also irritation and hyperemia (increased blood flow), the doses currently practicable in clinical tests are necessarily very low.
• the irritation experienced when PGF 2 ⁇ or its esters are applied, consists mainly in a feeling of grittiness or of having a foreign body in one's eye, this being usually accompanied by increased lacrimation.
• the prostaglandin derivatives have the general structure wherein A represents the alicyclic ring C 8 -C 12 and the bonds between the ring and the side chains represent the various isomers.
• A represents the alicyclic ring C 8 -C 12 and the bonds between the ring and the side chains represent the various isomers.
• PGB, PGD, PGE and PGF A has the formula
• the invention is based on the use of derivatives characterized by their omega chain and various modifications of the alpha chain is therefore possible still using the inventive concept.
• the alpha chain could typically be the naturally occuring alpha chain, which is esterified to the structure in which R 1 is an alkyl group, preferably with 1-10 carbon, especially 1-6 atoms, for instance metyl, ethyl, propyl, isopropyl, butyl, isobutyl, neopentyl or benzyl or a derivative giving the final substance equivalent properties as a glaucoma agent.
• the chain could preferably be a C 6 -C 10 chain which might be saturated or unsaturated having one or more double bonds, and allenes, or a triple bond and the chain might contain one or more substituents such as alkyl groups, alicyclic rings, or aromatic rings with or without hetero atoms.
• the omega chain is defined by the following formula: wherein
• the most preferred derivatives at present are those in which the omega chain of the prostaglandin has the 18,19,20-trinor form, and especially the 17-phenyl analogs, such as the 15-(R)-, 15-dehydro and 13,14-dihydro-17-phenyl-18,19,20-trinor forms.
• Such derivatives are represented by (3), (6), (7) and (9) in the formulas given in Table I.
• the prostaglandin is a derivative of PGA, PGD, PGE or PGF, especially of PGA 2 , PGD 2 , PGE 2 and PGF 2 ⁇
• the invention thus relates to the use of certain derivatives of PGA, PGB, PGD, PGE and PGF for the treatment of glaucoma or ocular hypertension.
• these derivatives defined above it has been found that some are irritating or otherwise not optimal, and in certain cases not even useful due to adverse effects and these are excluded in that the group of prostaglandin derivatives defined above is limited to therapeutically effective and physiologically acceptable derivatives. So is for instance (1) 16-phenyl-17,18,19,20-tetranor-PGF 2 ⁇ -isopropyl ester irritating while this can be eliminated by substituting the phenyl ring with a methoxy group giving formula (8) which represents a therapeutically more useful compound,
• the method for treating glaucoma or ocular hypertension consists in contacting an effective intraocular pressure reducing amount of a composition, as aforesaid, with the eye in order to reduce the eye pessure and to maintain said pressure on a reduced level.
• the composition contains 0.1-30 ⁇ g, especially 1-10 ⁇ g, per application of the active substance i.e. a therapeutically active and physiologically acceptable derivative from the group defined above; the treatment may advantageously be carried out in that one drop of the composition, corresponding to about 30 ⁇ l, is administered about 1 to 2 times per day to the patient's eye. This therapy is applicable both to human beings and to animals.
• the invention further relates to the use of therapeutically active and physiologically acceptable prostaglandin derivatives from the group defined above for the preparation of an ophthalmological composition for the treatment of glaucoma or ocular hypertension.
• the prostaglandin derivative is mixed with an ophthalmologically compatible vehicle known per se .
• the vehicle which may be employed for preparing compositions of this invention comprises aqueous solutions as e.g. physiological salines, oil solutions or ointments.
• the vehicle furthermore may contain ophthalmologically compatible preservatives such as e.g. benzalkonium chloride, surfactants like e.g.
• polysorbate 80 liposomes or polymers, for example methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone and hyaluronic acid; these may be used for increasing the viscosity. Furthermore, it is also possible to use soluble or insoluble drug inserts when the drug is to be administered.
• the invention is also related to ophthalmological compositions for topical treatment of glaucoma or ocular hypertension which comprise an effective intra ocular pressure reducing amount of a prostaglandin derivative as defined above and an ophthalmologically compatible carrier, the effective amount comprising a dose of about 0.1-30 ⁇ in about 10-50 ⁇ of the composition.
• the active compound in an amount, varying with potency of the drug, from 30 ⁇ g to 300 ⁇ g/ml was dissolved in a sterilized aqueous solution (saline 0.9 %) containing 0.5 % polysorbate-80 as solubilizing agent.
• Example 1 Preparation of 16-phenyl-17,18,19,20-tetranor PGF 2 ⁇ -isopropyl ester (1).
• Example 2 Preparation of 17-phenyl-18,19,20- trinor PGF 2 ⁇ -isopropyl ester (2).
• a 50 ml round bottom flask equipped with a magnetic stirring bar was charged whith 20 mg (0.05 mmol) 17-phenyl-18,19,20-trinor PGF 2 ⁇ (Cayman Chemicals), 6 ml acetone, 39.2 mg (0.25 mmol) DBU and 42.5 mg (0.25 mmol) isopropyl iodide.
• the solution was allowed to stand at room temperature for 24 h, the solvent was removed in vacuo and the residue was diluted with 30 ml of ethyl acetate, washed twice with 10 ml 5 % sodiumhydrogen carbonate and 10 ml 3 % citric acid.
• Example 4 Preparation of 16-phenoxy-17,18,19,20 -tetranor PGF 2 ⁇ -isopropyl ester(4).
• Example 5 Preparation of 17-phenyl-18,19,20-trinor PGE 2 -isopropyl ester (5).
• the reaction mixture was diluted with 10 g ice and 10 ml water and extracted with 2x50 ml ethyl acetate, whereafter the aqueous layer was cooled, acidified with HCl 1 M and extracted with ethyl acetate, and then the organic layer was dried and concentrated.
• the resulting crude product was a colourless substance.
• the purity of the title compound (17) was estimated by TLC on silica gel using ethyl acetate: acetone: acetic acid 1:1:0.2 v/v/v as eluent.
• the crude product (17) was esterified following a procedure similar to that described in example 2 the product was purified by column chromatography on silica gel-60 using ethyl acetate as eluent and the resulting mixture of C 15 epimeric alcohol were separated.
• Example 8 Preparation of 16-[4-(methoxy)phenyl]-17,18,19,20-tetranor PGF 2 ⁇ -isopropyl ester (8).
• step 7-2 Following a procedure similar to that described in example 7 with modified step 7-2, the aldehyde 12 described in step 7-2 was reacted with dimethyl-2-oxo-3-[4-(methoxy)phenyl]-propylphosphonate and was purified by column chromatography on silica gel-60 using ethyl acetate: toluene 1:1 as eluent. A colourless oily substance was obtained (57 % yield).
• Example 10 Preparation of 18-phenyl-19,20-trinor PGF 2 ⁇ -isopropyl ester (10).
• Example 11 Preparation of 19-phenyl-20-nor-PGF 2 ⁇ -isopropyl ester (20).
• the intraocular pressure (IOP) was determined in animals with a pneumatonometer (Digilab Modular OneTM, Bio Rad), specially calibrated for the eye of the particular species.
• the cornea was anaesthetized with 1-2 drops of oxibuprocain before each IOP measurement.
• IOP was measured with applanation tonometry or with an air puff tonometer (Keeler pulsair).
• a pneumatonometer Digilab
• Goldmann's applanation tonometer mounted on a slit lamp microscope was used for applanation tonometry.
• the cornea was anaesthetized with oxibuprocain before each measurement with applanation tonometry. No local anaesthesia was employed before measurement with the pulsair tonometer.
• the ocular discomfort after application of the test substances was evaluated in cats.
• the behaviour of cats after topical application of the test drug was followed and ocular discomfort was graded on a scale from 0 to 3, 0 indicating complete absence of any signs of discomfort, and 3 indicating maximal irritation as obvious from complete lid closure.
• Conjunctival hyperemia after topical application of the test substances was evaluated in rabbits.
• the conjunctiva at the insertion of the superior rectus muscle of the eye was inspected or photographed with regular intervals and the degree of hyperemia was later evaluated from the color photographs in a blind manner.
• Conjunctival hyperemia was evaluated on a scale from 0 to 4, 0 indicating complete absence of any hyperemia, and 4 indicating marked hyperemia with conjunctival chemosis.
• monkeys For determination of the effects on the intraocular pressure, primarily monkeys (cynomolgus) were employed. The reason for this is that the monkey eye is highly reminiscent of the human eye and therefor, generally, drug effects are readily extrapolated to the human eye.
• the disadvantage of using the monkey eye as a model is that the conjunctiva in this species is pigmented making it impossible to evaluate conjunctival hyperemia and furthermore, the monkey eye is relatively insensitive to irritation. Therefore, the cat eye, being very sensitive to prostaglandins was used for evaluating ocular discomfort and the rabbit eye with pronounced tendency to hyperemic reactions was used for evaluating conjunctival and episcleral hyperemia.
• modifying the omega chain and substituting a carbon atom in the chain with a ring structure introduces completely new, unexpected and advantageous qualities to naturally occuring prostaglandins in that the irritating effect in the conjunctiva and cornea is abolished.
• 16-phenyl--17,18,19,20-tetranor-PGF 2 ⁇ -IE exhibiting some irritating effect substituting a hydrogen atom in the ring structure with e.g. a methoxy group attenuates or abolishes the irritating effect.
• omega chain modified analogs In addition to the lack of ocular discomfort the omega chain modified analogs also exhibited an advantage over naturally occuring prostalgandins in that they caused considerably less conjunctival hyperemia as studied in the rabbit eye (Table IV). Particularly, 15-dehydro-17-phenyl-18,19,20-trinor-PGF 2 ⁇ -IE,13,14-dihydro-17-phenyl-18,19,20-trinor--PGF 2 ⁇ -IE, and 13,14-dihydro-17-phenyl-18,19,20-trinor PGA 2 -IE were adventageous in this respect. Also 18-phenyl--19,20-dinor-PGF 2 ⁇ -IE and 19-phenyl-20-nor-PGF 2 ⁇ -IE induced very little conjunctival hyperemia (TableIV).
• omega chain modified prostaglandin analogs more specifically 17-phenyl-18,19,20-trinor-PGF 2 ⁇ -IE, 15-dehydro-17-phenyl-18,19,20-trinor-PGF 2 ⁇ -IE, 15-(R)-17-phenyl-18,19,20-trinor-PGF 2 ⁇ -IE, 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF 2 ⁇ -IE, and 18-phenyl-19-20-dinor-PGF 2 ⁇ -IE on the intraocular pressure of healthy human volunteers is demonstrated in Table VI. All compounds significantly reduced the intraocular pressure.
• the present invention thus describes a group of compounds exhibiting the unique property of causing insignificant ocular side effects while retaining the intraocular pressure lowering effect. From the foregoing it is evident that the crucial modification of the molecule is a ring structure in the omega chain. Furthermore, substituents in the ring structure and/or in the omega chain may be introduced in certain molecules still exhibiting some side-effects in the eye. Hetero atoms may also be introduced into the ring substituted omega chain. Presently, particularly 17-phenyl-18,19,20-trinor-PGF 2 ⁇ -derivatives seem very promising for therapeutic use in glaucoma.
• Substance Dose ( ⁇ g) Degree of hyperemia PGF 2 ⁇ -isopropylester (-IE) 0.1 2.8 ⁇ 0.2 15-propionate-PGE 2 -IE 0.5 2.7 ⁇ 0.3 16-phenyl-17,18,19,20- tetranor-PGF 2 ⁇ -IE (1) 0.5 1.3 ⁇ 0.9 17-phenyl-18,19,20-trinor- PGF 2 ⁇ -IE (2) 0.5 2.0 ⁇ 0.3 15-dehydro-17-phenyl- 18,19,20-trinor-PGF 2 ⁇ -IE (3) 0.5 0.7 ⁇ 0.3 15-(R)-17-phenyl-18,19,20- trinor-PGF 2 ⁇ -IE (7) 0.5 2.0 ⁇ 0.0 13,14-dihydro-17-phenyl- 18,19,20-trinor-PGF 2 ⁇ -IE (9) 0.5 1.3 ⁇ 0.3 17-phenyl-18,19,20-trinor- PGE 2 -IE
• Prostaglandin F 2 ⁇ -1-isopropylester lowers intraocular pressure without decreasing aqueous humor flow. Am J Ophthalmol 105:30-34.

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